Process of halogenating organic compounds



United States Patent ruocuss OFVIIALOGENATING ORGANIC comounos Albert J.Boyle, Detroit, Mich., and Albert Zlatkis, Houston, Tex ass lgnors toBasic, Incorporated, a corporation ofOhio i No Drawing. ApplicationFebruary 25, 1954 Serial: No. 412,620

1 Claim. "(Cl. 260519) -Variousmethodsof halogenating organic compoundshave been suggested or are in use, and involvingvarious halogenatlngreagents. A difficulty which has persisted in many cases is lossofmaterials, and the obtaining of lower chlorination of toluene, moreorthochlorotoluene is produced than parachlorotoluene, whereas in thechlorination of toluene by other processes the parachlorotoluene is thechief product. Other objects and advantages will appear from thefollowing description.

To the accomplishment of the foregoing and related ends, said invention,then, comprises the features hereinafterfully described and particularlypointed out in the claim, the following description setting forth indetail certain illustrative embodiments ofthe invention, these beingindicative, however, of but a few of the variousways in which theprinciple of the invention may be employed.

In'general, the presentprocess involves halogenating acceptor compoundsby reaction to formation ot'a halogen compound-thereof plus by-productwater, by treating with a reaction medium containing apentavalenthalogen of higher atomic weight than fluorine, in acid medium providingin addition halide, and hydrogen ions. Halogenation proceeds by thisprocess uniformly, and in many instances even though the organiccompound to be halogenated is only partially soluble in the solventphase containing the otheringredients. To a mechanically agitatedmixture of solvent, usually water, the. organic compound to behalogenated, and an acid furnishing hydrogenions and a halide, theoxyhalide salt or oxyhalide acid is added. Thus, with. a mixture forinstance of water and the organic compound to be halogenated, a suitableamount of an acid, a source of halide, and a small amount of a catalyst,such as for instance, a soluble iron salt furnishing ferric or ferrousions, e. g., Fecl FeSO Fe(NO FeOH(C H O etc., 100 to .300 milligrams perliter, the oxyhalide or oxyhalide acid is added, the mixture beingthoroughly agitated, and the temperature controlled. The halogenatedproduct is obtained in good yield for instance by a single distillationor recrystallization of the crude product.

A variation is the use of the oxyhalide asacid or salt present in fullamount with the organic compound to be halogenated, water, mineral ororganic acid and cata lyst. To this agitated mixture at properlycontrolled temperature a halide or acid of the halide is added slowlyand uniformly to the reaction mixture.

The present process is effective in the halogenation of carbon chaincompounds having directional groups, that is aromatic, heterocyclic,aliphatic and alicyclic compounds which possess functional groups Whichare of a pirectional or determinative nature in halogenation or otheringredients of the reaction.

other reactions. Such directional groups are alkyl, carboxy1,.hydroxyl,amino, substituted amino,.phenoxy, and aliphatic .ethers. Such variouscompounds. are typified by: tol uene, xylene, mesitylene, benzoic acid,salicylic acid,. beta-re sorcylic acid, 1-4 benzoquinone, resorcinol,

methyl phenyl ether, ethyl phenyl ether, resorcinol dimethyl ether,.diphenyl ether, S-hydroxyquinolin, ,ai1- hranilic acid, l-tyrosine,stearic acid and cyclohexanol.

As. oxyhalide salt or oxyhalide acid, depending iupon the particularhalogenation to be accomplished, whether chlorination, bromination oriodination, there V may be employed an oxyacid of the halogen or anoxyhalide salt, such as oxychloride, an oxybromide, or an oxyiodidewhich. the halogen is in the .pentavalent state. As oxyhalide salts,those ofthe group consisting of alkaliand alkaline earth rnetals areapplicable. It is also possible to halogenate with an oxyhalide whosehalogenis not represented in the final halogenated organic compoundorproduct. Thus chlorination, for example, maybe accomplished by theslow and unifrom addition of an iodate oriodic acid to an agitatedmixture at properly C OHt IYOilCLl temperature containing the organiccompound to be chlorinated, water, a source of hydrogen ion, chloridesalt or hydrochloric acid, and to 300 mg. of iron salt ,per

.C. are employed. This is also true in bromination reactions using bronates. it may be generally stated that in the event the oxyhalide isunstable by itself due to temperature or excessive acidity or acombination of both or in the presence of reactants before allingredients are introduced (except halide salt or halideacid) it is bestadded from the outside slowly and uniformly to all the In general, therange of operative temperatures is 0 C. to just below C. The optimumtemperature of reaction is somewhatde pendent in each case on the natureof the organic compound being halogenated and the halogenating agents orboth. For example, the bromination of toluene requires a temperature inthe neighborhood of 20 C.; the iodination of tyrosine a temperature ofapproximately 45 C. and the iodination of toluene a temperature of .90C. in other words, wasteful decomposition of the halogenating agents dueto temperature or undesirable decomposition or alteration of the organicmaterial before, during orafter halogenation is to be avoided.

The acid to supply the hydrogen ions is usually hydrochloricacid orsulphuric acid or phosphoric acid, although in the case of rather easilydecomposed organic compounds to be halogenated, a weaker acid, such asacetic acid or the previously mentioned mineral acids in reducedconcentration are preferred. Depending upon the nature of the compoundbeing halogenated and the halogen being introduced into themolecule, therange of initial acid concentration varies in the instance ofhydrochloric acid between 7 and 37% H01 by weight, in that of sulphuricacid between 5 and 40% H 80 by weight, and in --that .of acetic acidbetween 5 and 30% CH -COOH by weight. During the course of the reaction,the formation of water reduces the concentration slightly. Other organicacids, such as formic are too reactive with the halogenating agents tobe used as a source of hydrogen ions.

In the case of iodination the present process has very importantadvantages over the practice heretofore. Primarily, the process is asimple one-step reaction using readily available starting materials; andsecondl the products obtained are relatively pure, requiring only onecrystallization. Finally, and very important from the practicaleconomical point of view, essentially all of the iodine liberated isused to iodinate the compound.

For chlorination then, a chlorate ion, e. g., chloric acid or sodiumchlorate, is added slowly and uniformly to the mixture of the solvent,the organic compound to be chlorinated, hydrochloric acid, and a smallamount of iron salt as aforementioned, the temperature for the reactionbeing maintained below boiling point, such as 60 to 90 C. Inbrominating, to a mixture of solvent, e. g., water, the organic compoundto be brominated, bromic acid or a bromate salt, sulphuric acid insuitable amount, and a small amount of iron salt as aforementioned,there is added slowly at bromide salt, which may be in water solution.Above a temperature of 40 C. a bromate may be added from the outside toa mixture of bromide salt, water, acid, catalyst, and organic com poundto be brominated. In the case of iodination, again a mixture of solvent,the organic compound to be iodinated, iodic acid or an iodate, an acidand a small amount of iron salt as afore-mentioned, is mechanicallyagitated and heated to a temperature range as aforestated, and an iodidesalt is added, in water solution.

The following examples are illustrative (the equations writtenconsidering the oxyhalide and halides as acid):

I. Add together in a 1000 ml. Pyrex flask equipped with condenser,stirrer and dropping funnel 92 grams (1 mol) of toluene, 100 ml. ofconcentrated HCl, a small amount of iron salt, e. g., 100 mg. and 50 ml.of water. Agitate the mixture vigorously and heat to 70 C. Add dropwiseto the agitated mixture a solution consisting of 48 grams of sodiumchlorate and 125 ml. of water. The crude product of chlorotoluene iseasily separated from the reaction mixture and may be distilled at157-162 C. It is to be noted that in this type reaction the oxyhalide isadded to the other substances during the course of the reaction. Ageneral reaction is:

II. Add together in a 1 liter Pyrex flask equipped with condenser,stirrer and dropping funnel, 92 grams (1 mol) of toluene, 53 grams (0.35mol) sodium bromate, 200 ml. of water containing 80 ml. of concentratedsulphuric acid which has been cooled to room temperature and a smallamount of iron salt as foregoing. Agitate the mixture vigorously and adddropwise to the reaction flask at room temperature a solution consistingof 72 grams (0.7 mol) sodium bromide in 125 ml. of water. In order tomaintain the temperature of the reaction between 20 and 30 C. it may benecessary to use an ice bath. In the course of two or three hours thebromide salt is added dropwise as described. The agitated mixture isthen raised slowly to 85 C. and permitted to remain there for one-halfhour. The crude bromotoluene is easily separated from the mixture,cooled and washed twice in a separatory funnel with cold 1% sodiumhydroxide. It is then distilled under vacuum at 38 C. and 1.5 mm. Hgpressure. The yield obtained (bromotoluene) is approximately 50%. It isnoticed that in this example all of the oxyhalide is present in theheated mixture to which the bromide is added slowly throughout thecourse of the reaction. In the presence of sufficient acid, the reactionmay be represented as follows:

'4 III. Add together in a 1000 m1. Pyrex flask equipped with condenser,stirrer and dropping funnel 92 grams (1 mol) of toluene, 66 grams (0.33mol) sodium iodate, 300 ml. H 0, ml. concentrated H 80 and a smallamount of iron salt. Agitate the mixture vigorously and heat to C. Adddropwise to the agitated mixture a solution consisting of grams (0.66mol) of sodium iodide and 100 ml. of water. The crude product,iodotoluene, is easily separated from the reaction mixture and may bedistilled under vacuum, 5556 C./0.75 mm. Hg. It is to be noted in thistype reaction the oxyhalide is present in full amount in the reactingmixture to which iodide is added dropwise during the course of thereaction. The

reaction may be represented as:

lV. A mixture containing 27 grams (0.149 mol) of l.- tyrosine and 500ml. of 15% acetic acid is heated to 45 C. (somewhat higher or lowertemperatures may be employed). The mixture is mechanically agitatedwhile a dropwise addition of a water solution containing 25 grams (0.126mole) of NalO and 33 grams (0.22 mole) of NaI is made. A reaction timeof three quarters of an hour is usually required for the above systemand the product, usually straw yellow, is obtained in yields of 8090%.Recrystallization from 10% acetic acid (char coal) yields a productdecomposing between 191-195 C. Vacuum drying this product for severalhours at 100 C. yields a product which decomposed between 202-204 C. Thereaction may be represented as follows:

A 80-90% yield of 3,5-diiodo-1-tyrosine may be isolated. It is noticedthat at no time is the tyrosine or iodinated product completely insolution. Complete solubility of the organic molecule to be halogenatedis not necessary for a successful reaction. All of the iodine liberatedgoes into iodinating the compound. The oxyiodide salt immediatelyoxidizes any hydrogen iodide formed, thereby preventing anyde-iodination.

Other modes of applying the principle of the invention may be employed,change being made as regards the details described, provided thefeatures stated in the following claim or the equivalent of such beemployed.

We therefore particularly point out and distinctly claim as ourinvention:

The method of making iodo-tyrosine which comprises agitating a mixtureof l-tyrosine and acetic acid at a temperature of approximately 45 C.,gradually adding to such mixture while thus agitated a water solution ofsodium iodate and iodide, and then separating the resulting3,5-diodo-1-ty1osine from the reacting mixture.

References Cited in the file of this patent UNITED STATES PATENTSl,741,305 Iaeger Dec. 31, 1929 2,417,027 Weinmayer Mar. 4, 19472,535,131 Gubelmann Dec. 26, 1950 OTHER REFERENCES Groggins: UnitProcesses in Organic Synthesis, fourth edition, pages 177 and 214-218(1952).

1. THE METHOD OF MAKING IODO-TRYROSINE WHICH COMPRISES AGITATING AMIXTURE OF 1-TYROSINE AND ACETIC ACID AT A TEMPERATURE OF APPROXIMATELY45*C., GRADUALLY ADDING TO SUCH MIXTURE WHILE THUS AGITATED A WATERSOLUTION OF SODIUM IODATE AND IODIDE, AND THEM SEPARATING THE RESULTING3,5-DIODO-1-TYROSINE FROM THE REACTING MIXTURE.